The invention relates to non-aqueous, particle-forming pharmaceutical compositions containing fused pyrrolocarbazoles or derivatives thereof. The invention is also directed to stable solutions which result upon contacting the particle-forming compositions of the present invention with an aqueous medium. The invention is further directed to methods of medical treatment which include treatment of a subject with the compositions or solutions of the present invention.
Fused pyrrolocarbazoles display various pharmacological activities. For example, fused pyrrolocarbazoles are useful for treatment of neurological diseases or disorders, and some display antifungal, antimicrobial, or antitumor activity. In some cases this is accomplished by modulation of neurotrophic responses through effects on protein kinase activity (Berg et al., J. Biol. Chem. 267:13-16 (1992)). Fused carbazoles and their derivatives have been isolated from a various microorganisms, including S. staurosporeus, N. aerocoligenes, Actinomadura and Nocardiopsis sp, (Kase et al., Biochem. Biophys. Res. Commun. 142: 436-440, (1987)).
Specific fused pyrrolocarbazoles, such as indolocarbazoles, which have been characterized include the following: staurosporine and rebeccamycin (Moody et al., supra); K-252a, K-252b (Kase et al., supra); K-252c (also called staurosporine aglycon) (Moody et al., supra), K-252d and derivatives thereof (published Japanese patent applications 60-257652, 60-295172, 62-327858, 62-327859, and 60-295173). K-252a, K-252b, K-252c, and K-252d are insoluble in water (Nakanishi et al., J. Antibodies, 34:1066, (1986)).
In general, fused pyrrolocarbaezoles display very low water solubility. Dry pharmaceutical preparations (dragees, tablets and capsules) of staurosporine derivatives that may contain polyethylene glycol and polyvinylpyrrolidone have been described in U.S. Pat. No. 5,093,330. Conventional pharmaceutical formulations that include indolocarbazoles are described in U.S Pat. No. 5,043,335 and PCT publication No. WO 93/00909. Aqueous indolocarbazole compositions are described in U.S. Pat. No. 5,599,808.
Self-emulsifying drug delivery systems (xe2x80x9cSEDDSxe2x80x9d) have been developed for drugs that display very low water solubility but good oil solubility. See, e.g., Shah et al., International Journal of Pharmaceutics (Netherlands) 106:15-23, (1994). Despite their low water solubility, fused carbazoles are generally unsuited for SEDDS because of their low oil solubility.
Accordingly, one object of the present invention is to provide particle-forming compositions containing fused pyrrolocarbazoles or derivatives thereof. Particularly, the compositions of the present invention are non-aqueous and contain an amount of surfactant sufficient to make an fused pyrrolocarbazole or a derivative thereof particle-forming.
It is another object of the invention to provide a stable suspension that comprises suspended fused pyrrolocarbazole-containing particles that greatly improves bioavailability upon oral administration.
It is another object of the invention to provide a method of forming a stable suspension of fused pyrrolocarbazole-containing particles which comprises contacting the particle-forming compositions of the present invention with an aqueous medium.
It is another object of the invention to provide a method of treating a disease or disorder in a mammal which comprises administering a therapeutically effective amount of the particle-forming compositions of the present invention.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventor""s discovery that fused pyrrolocarbazoles and derivatives thereof can be formulated with suitable concentrations of one or more surfactants to make a non-aqueous, particle-forming composition, wherein the composition spontaneously disperses into suspended particles upon contact with an aqueous medium.
Thus, in a first embodiment, the present invention provides a non-aqueous, particle-forming composition comprising a fused pyrrolocarbazole and a surfactant. In a preferred embodiment, the fused pyrrolocarbazole has Formula I: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
ring B and ring F, are independently selected from:
a) an unsaturated 6-membered carbocyclic aromatic ring in which from 1 to 3 carbon atoms may be replaced by nitrogen atoms;
b) an unsaturated 5-membered carbocyclic aromatic ring; and
c) an unsaturated 5-membered carbocyclic aromatic ring in which either:
1) one carbon atom is replaced with an oxygen, nitrogen, or sulfur;
2) two carbon atoms are replaced with a sulfur and a nitrogen, an oxygen and a nitrogen, or two nitrogens; or
3) three carbon atoms are replaced with three nitrogens;
Gxe2x80x94Xxe2x80x94W is selected from:
a) xe2x80x94(Z1Z2)Cxe2x80x94N(R1)xe2x80x94C(Z1Z2)xe2x80x94;
b) xe2x80x94CH(R1)xe2x80x94C(xe2x95x90O)xe2x80x94N(R1)xe2x80x94; and
c) xe2x80x94N(R1)xe2x80x94C(xe2x95x90O)xe2x80x94CH(R1)xe2x80x94;
Z1 and Z2, at each occurrence, are independently selected from H, H; H, OR; H, SR; H, N(R)2; and a group wherein Z1 and Z2 together form a moiety selected from xe2x95x90O, xe2x95x90S, and xe2x95x90NR; with the proviso that at least one of the pairs Z1 and Z2 form xe2x95x90O;
R is selected from H, substituted or unsubstituted alkyl having from 1 to 6 carbons, OH, alkoxy having from 1 to 4 carbons, OC(xe2x95x90O)R1a, OC(xe2x95x90O)NR1cR1d, O(CH2)pR1cR1d, O(CH2)pOR1b, substituted or unsubstituted arylalkyl having from 6 to 10 carbons, and substituted or unsubstituted heteroarylalkyl;
R1 is selected independently from:
a) H, substituted or unsubstituted alkyl having from 1 to 6 carbons, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substitute or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl;
b) C(xe2x95x90O)R1a;
c) OR1b;
d) C(xe2x95x90O)NHR1b, NR1cR1d, (CH2)pNR1cR1d, (CH2)pOR1b, O(CH2)pOR1b and O(CH2)pNR1cR1d;
R1a is selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl and heteroaryl;
R1b is selected from H and substituted or unsubstituted alkyl having from 1 to 6 carbons;
R1c and R1d are each independently selected from H, substituted or unsubstituted alkyl having from 1 to 4 carbons, and a linking group of the formula xe2x80x94(CH2)2xe2x80x94X1xe2x80x94(CH2)2xe2x80x94;
X1 is selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, and xe2x80x94CH2xe2x80x94;
R2 is selected from H, SO2R2a, CO2R2a, C(xe2x95x90O)R2a, C(xe2x95x90O)NR2cR2d, and alkyl of 1-8 carbons, alkenyl of 2-8 carbons, alkynyl of 2-8 carbons, wherein:
1) each alkyl, alkenyl, and alkynyl is unsubstituted; or
2) each alkyl, alkenyl, and alkynyl is substituted with 1-3 R5;
R2a is selected from alkyl of 1 to 6 carbons, aryl, OR CONH2, NR2cR2d, (CH2)pNR2cR2d, and O(CH2)pNR2cR2d;
R2b is selected from H and substituted or unsubstituted alkyl having from 1 to 6 carbons;
R2c and R2d are each independently selected from H, substituted or unsubstituted alkyl having from 1 to 6 carbons, and a linking group of the formula xe2x80x94(CH2)2xe2x80x94X1xe2x80x94(CH2)2xe2x80x94;
R3 and R4, at each occurrence, are independently selected from:
a) H, aryl, heteroaryl, F, Cl, Br, I, CN, CF3, NO2, OH, OR9, O(CH2)pNR11R12, OC(xe2x95x90O)R9, OC(xe2x95x90O)NR11R12, O(CH2)pOR10, CH2OR10, NR11R12, NR10S(xe2x95x90O)2R9, and NR10C(xe2x95x90O)R9;
b) CH2OR14;
c) NR10C(xe2x95x90O)NR11R12, CO2R10, C(xe2x95x90O)R9, C(xe2x95x90O)NR11R12, CHxe2x95x90NOR10, CHxe2x95x90NR10, (CH2)pNR11R12, (CH2)pNHR14, and CHxe2x95x90NNR11R12;
d) S(O)yR9, (CH2)pS(O)yR9, CH2S(O)yR14;
e) alkyl having from 1 to 8 carbons, alkenyl having from 2 to 8 carbons, and alkynyl having 2 to 8 carbons, wherein
1) each alkyl, alkenyl, or alkynyl group is unsubstituted; or
2) each alkyl, alkenyl, or alkynyl group is substituted with 1 to 3 R5;
R5 is selected from aryl having from 6 to 10 carbons, heteroaryl, arylalkoxy, heterocycloalkoxy, hydroxyalkoxy, alkyloxy-alkoxy, hydroxyalkylthio, alkoxy-alkylthio, F, Cl, Br, I, CN, NO2, OH, OR9, X2(CH2)pNR11R12, X2(CH2)pC(xe2x95x90O)NR11R12, X2(CH2)pOC(xe2x95x90O)NR11R12, X2(CH2)pCO2R9, X2(CH2)pS(O)yR9, X2(CH2)pNR10C(xe2x95x90O)NR11R12, OC(xe2x95x90O)R9, OC(xe2x95x90O)NHR10, O-tetrahydropyranyl, NR11R12, NR10C(xe2x95x90O)R9, NR10CO2R9, NR10C(xe2x95x90O)NR11R12, NHC(xe2x95x90NH)NH2, NR10S(O)2R9, S(O)yR9, CO2R10, C(xe2x95x90O)NR11R12, C(xe2x95x90O)R9, CH2OR10, CHxe2x95x90NNR11R12, CHxe2x95x90NOR10, CHxe2x95x90NR9, CHxe2x95x90NNHCH(Nxe2x95x90NH)NH2, S(xe2x95x90O)2NR11R12, P(xe2x95x90O)(OR10)2, OR14, and a monosaccharide having from 5 to 7 carbons wherein each hydroxyl group of the monosaccharide is independently either unsubstituted or is replaced by H, alkyl having from 1 to 4 carbons, alkylcarbonyloxy having from 2 to 5 carbons, or alkoxy having from of 1 to 4 carbons;
X2 is O, S, or NR10;
Q is selected from:
1) NR6;
2) an unsubstituted alkylene of 1-3 carbons;
3) a substituted alkylene of 1-3 carbons;
4) CHxe2x95x90CH, CH(OH)CH(OH), O, S, S(xe2x95x90O), S(xe2x95x90O)2, C(xe2x95x90O), C(xe2x95x90NOR11), C(OR11)(R11), C(xe2x95x90O)CH(R13), CH(R13)C(xe2x95x90O), C(R10)2, C(xe2x95x90NOR11)CH(R13), CH(R13)C(xe2x95x90NOR11), CH2Z, Zxe2x80x94CH2, CH2ZCH2;
Z is selected from C(R11)(OR11), O, S, C(xe2x95x90O), C(xe2x95x90NOR11), and NR11;
R6 is selected from H, SO2R2a, CO2R2a, C(xe2x95x90O)R2a, C(xe2x95x90O)NR1cR1d, and alkyl of 1-8 carbons, alkenyl of 2-8 carbons, alkynyl of 2-8 carbons, wherein:
1) each alkyl, alkenyl, and alkynyl is unsubstituted;
2) each alkyl, alkenyl, and alkynyl is substituted with 1-3 R5; or
alternatively, when Q is NR6 or C(R10)2, R6 or one R10 joins with R2 to form: 
wherein R7 and R8 are each independently selected from H, OH, alkyl having from 1 to 6 carbons, alkoxy having from 1 to 6 carbons, substituted or unsubstituted arylalkyl having from 6 to 10 carbons, substituted or unsubstituted heteroarylalkyl, (CH2)pOR10, (CH2)pOC(xe2x95x90O)NR11R12, and (CH2)pNR11R12; or
R7 and R8 together form a linking group of the formula CH2xe2x80x94X3xe2x80x94CH2;
X3 is a bond, O, S, or NR10;
R9 is selected from alkyl having 1 to 6 carbons, (CH2)raryl and (CH2)rheteroaryl;
R10 is selected from H, alkyl having from 1 to 6 carbons, (CH2)raryl and (CH2)rheteroaryl;
R11 and R12, at each occurrence, are independently selected from:
1) H and substituted or unsubstituted alkyl having from 1 to 6 carbons; or
2) R11 and R12 together form xe2x80x94(CH2)2xe2x80x94X1xe2x80x94(CH2)2xe2x80x94;
Y is selected from O, S, N(R10), N+(Oxe2x88x92)(R10), N(OR10), and CH2;
J is selected from the group consisting of a bond, O, CHxe2x95x90CH, S, C(xe2x95x90O), CH(OR10), N(R10), N(OR10), CH(NR11R12), C(xe2x95x90O)N(R17), N(R17)C(xe2x95x90O), N(S(O)yR9), N(S(O)NR11R12), N(C(xe2x95x90O)R17), C(R15R16), N+(Oxe2x88x92)(R10), CH(OH)CH(OH), and CH(O(Cxe2x95x90O)R9)CH(OC(xe2x95x90O)R9);
R13 is selected from alkyl having from 1 to 4 carbons, aryl, and arylalkyl having from 7 to 14 carbons;
R14 is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;
R15 and R16, at each occurrence is selected from H, OH, C(xe2x95x90O)R10, O(Cxe2x95x90O)R9, alkyl-OH, and CO2R10;
R17 is selected from the group consisting of H, alkyl, aryl, and heteroaryl;
m and n are independently selected from 0, 1, and 2;
p is independently selected from 1, 2, 3, and 4;
r is independently selected from 0, 1, and 2; and
y is independently selected from 0, 1 and 2.
In certain preferred embodiments, rings B and F are phenyl. In other preferred embodiments, Gxe2x80x94Xxe2x80x94W is selected from CH2NR1C(xe2x95x90O), C(xe2x95x90O)NR1CH2, and C(xe2x95x90O)NR1C(xe2x95x90O). In other preferred embodiments, Q is NR6.
In other preferred embodiments, the fused pyrrolocarbazole has the Formula II-a: 
In certain more preferred embodiments, Z1 and Z2 are H, R3 and R4 are selected from H, alkyl, Cl, Br, CH2OH, CH2SOCH2CH3, CH2SO2CH2CH3, NHCONHC6H5, CH2SCH2CH3, CH2SC6H5, NHCO2CH3, CH2OC(xe2x95x90O)NHCH2CH3, N(CH3)2, CHxe2x95x90NNH, CH2N(CH3)2, CH2OCH2CH3, R7 is selected from H and alkyl, and R15 and R16 are independently selected from H, alkyl, OH, CH2OH, alkoxy, and CO2alkyl. In certain even more preferred embodiments, the fused carbazoles are indolocarbazoles as set forth in Tables 1-A and 1-B.
In certain preferred embodiments, the particle-forming composition further comprises one or more of an organic solvent, a lipid, or an antioxidant. In certain preferred embodiments, the amount of surfactant is at least about 20% (w/w). In certain more preferred embodiments, the amount of surfactant is at least 40% about (w/w). In certain more preferred embodiments, the amount of surfactant is at least about 50% (w/w).
In certain preferred embodiments, the surfactant is selected from polyethylene glycol stearate, d-xe2x88x9d-tocopheryl polyethylene glycol succinate, poloxy stearate, poloxy castor oil, a polyoxyethylene sorbitan fatty acid ester, a polyethylene glycol ether, a saturated polyglycolized glyceride, a fatty acid ester of polyethylene glycol, a hydroxylated lecithin, a medium chain monoglyceride, a medium chain fatty acid ester, and polyethylene-propylene glycol copolymer. In other preferred embodiments, the lipid is a diester of coconut fatty acids and propylene glycol. In other preferred embodiments, the organic solvent is selected from propylene glycol, propylene carbonate, dimethyl isosorbide, and polyethylene glycol (PEG). In other preferred embodiments, the antioxidant is selected from ascorbic acid, a fatty acid ester of ascorbic acid, and butylated hydroxyanisole.
In certain preferred embodiments, the fused pyrrolocarbazole is present at a concentration of about 1 to about 300 mg/ml. In certain more preferred embodiments, the fused pyrrolocarbazole is present at a concentration of about 1 to about 100 mg/ml. In certain further more preferred embodiments, the concentration is about 1 to about 50 mg/ml.
In certain embodiments, the composition is a semi-solid or solid at room temperature. In certain more preferred embodiments, the semi-solid or solid is in the form of a capsule or tablet.
In another embodiment, the present invention provides a stable suspension of fused pyrrolocarbazole-containing particles in an aqueous suspension medium. In certain preferred embodiments, the particles have a diameter less than about 400 nm. In certain more preferred embodiments, the particles have a diameter less than about 100 nm.
In another embodiment, the present invention provides a method of forming a stable suspension of fused pyrrolocarbazole-containing, suspended particles, comprising contacting a fused pyrrolocarbazole in a non-aqueous liquid containing a surfactant in an amount from about 20% to greater than 99% with an aqueous medium. In a preferred method the particle-forming composition is contacted with an aqueous medium in vitro. In another preferred method, the particle-forming composition is contacted with an aqueous medium in vivo.
In another embodiment, the present invention provides a method of forming a stable suspension of fused pyrrolocarbazole-containing, suspended particles, comprising:
(a) dissolving a fused pyrrolocarbazole in a non-aqueous liquid containing a surfactant in an amount from about 20% to greater than 99%, to form a particle-forming composition; and
(b) contacting the particle-forming composition with an aqueous medium to form a stable suspension.
In another embodiment, the present invention provides a method of treating a disease or disorder in a mammal, comprising administering a therapeutically effective amount of a fused pyrrolocarbazole in a non-aqueous, particle-forming composition comprising a surfactant in an amount of at least 20% (w/w) to the mammal.
In another embodiment, the present invention provides a method of treating a disease or disorder in a mammal, comprising:
(a) contacting a fused pyrrolocarbazole in a non-aqueous, particle-forming composition comprising a surfactant in an amount of at least 20% (w/w) with an aqueous medium, thereby forming a stable suspension comprising suspended particles; and
(b) administering a therapeutically effective amount of the stable suspension to the mammal.
In certain preferred embodiments the surfactant is present in at least 40% (w/w). In other preferred embodiments, the disease or disorder is a neurological disorder, or cancer such as prostate cancer. In other preferred embodiments, the subject is a mammal.
The materials, methods, and examples presented herein are intended to be illustrative, and tot intended to limit the scope of the invention. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. Unless otherwise defined, all technical and scientific terms are intended to have their art-recognized meanings.
The present invention is directed to non-aqueous, particle-forming compositions which contain a fused pyrrolocarbazole, and a surfactant. Upon contact with an aqueous medium, the particle-forming composition spontaneously disperses into suspended particles, thereby forming a stable suspension that provides greatly improved bioavailability of orally administered fused pyrrolocarbazole compounds.
The particle-forming compositions of the present invention may be a liquid, semi-solid, or solid at room temperature. If liquid, the composition may be contained in a capsule. If semi-solid or solid, the composition can be in the form of a capsule or tablet.
As used herein, xe2x80x9cnon-aqueousxe2x80x9d composition is intended to mean a composition that contains from 0% to about 10% water by weight. As used herein, xe2x80x9cparticle-forming compositionxe2x80x9d is intended to mean a composition that spontaneously disperses into suspended particles upon entry into an aqueous medium. As used herein, xe2x80x9csuspended particlexe2x80x9d is intended to mean a micelle, microsphere, droplet, or other substantially non-crystalline physical structure that remains suspended in an aqueous medium, without substantial phase separation. As used herein, xe2x80x9caqueous mediumxe2x80x9d is intended to mean any medium comprised of greater than 10% water, and in which the compositions of the present invention are particle-forming.
Initially, a fused pyrrolocarbazole is dissolved in a non-aqueous, particle-forming composition. Subsequently, the particle-forming composition is contacted with an aqueous medium to form an aqueous suspension. Upon contact with an aqueous medium, the fused pyrrolocarbazole-containing, non-aqueous, particle-forming composition spontaneously forms particles of a suitable size, i.e., without energy input. Thus, when initially dissolved in a non-aqueous, particle-forming composition, a fused pyrrolocarbazole may have a higher solubility as compared to its solubility when placed directly in a comparable aqueous suspension containing preformed particles.
The particle-forming composition can be contacted with an aqueous medium in vitro, i.e., subjected to predilution, prior to ingestion by a mammal. Alternatively, the initial contact with an aqueous medium can be in vivo, e.g., contact with aqueous contents of the gastrointestinal composition of a mammal.
When the particle-forming composition is subjected to predilution, the dilution ratio preferably is from about 1:1000 (1 part formulation to 999 parts aqueous medium) to about 1:2 (1 part formulation to 1 part aqueous medium). More preferably, the dilution ratio is from about 1:500 (1 part formulation to 499 parts aqueous medium) to about 1:3 (1 part formulation to 2 parts aqueous medium). By way of general guidance, for administration to humans a convenient ratio is about 1:250, which is a rough correspondence to a 1 ml unit dose dispersed in an 8-ounce glass of an aqueous liquid.
It has also been discovered that the resultant solution in which the fused pyrrolocarbazole-containing particles are suspended is a stable suspension. Preferably, the particles contained in this medium have a diameter less than 400 nm. More preferably, the particles have a diameter less than 100 nm.
The degree of optical transparency of a given volume of water containing a given amount of formulation gives a useful indication of particle size. This is because the particles scatter visible light, with the larger particles causing greater scattering. In general, the greater the optical transparency, the smaller the particle size. High optical transparency, i.e., bluish haze invisible or nearly invisible, generally indicates a particle size of less than 100 nm. A distinct bluish haze generally indicates a particle size from about 100 nm to about 400 nm. Without intending to be bound by theory, it is noted that particle size tends to be essentially constant for a given formulation, regardless of the dilution ratio. If particles fail to form, an increase in dilution ratio may be used to promote particle formation.
Whether a formulation according to the invention is a liquid, semi-solid, or solid at room temperature, may depend upon the selection of components, or other concerns such as commercial viability, administration and the like. For example, a semi-solid or solid formulation is convenient for manufacturing unit doses of a fused pyrrolocarbazole in the form of a capsule, including both hard gelatin and soft gelatin capsules, and tablets. When the liquid or solid formulation contacts an aqueous medium, e.g., gastrointestinal liquids, the formulation disperses into suspended particles in which the fused pyrrolocarbazole is biologically available.
Compositions whose inert components (i.e., components other than the fused pyrrolocarbazole) are all liquid at room temperature can be prepared by simply mixing the components without heating. The desired amount of fused pyrrolocarbazole can be weighed out and dissolved in the mixture of inert components, without heating. Moderate heating, preferably less than 60xc2x0 C., can be applied to hasten complete mixing of the inert components, to hasten dissolution of the fused pyrrolocarbazole, or both.
Preparation of compositions containing one or more components that are solid at room temperature is carried out at a moderately elevated temperature, preferably less than 60xc2x0 C. While moderate heating can be useful, excessive heating can cause decomposition of one or more components of the formulation. For example, decomposition of polysorbate 80 can occur at temperatures above 60xc2x0 C. Instability of certain fused pyrrolocarbazoles has been observed in the presence of short chain polyethylene glycols, e.g., PEG 400, at temperatures in the range of about 60xc2x0 C. to 90xc2x0 C.
Decomposition of polysorbate 80 may occur if maintained at 90xc2x0 C. for more than one hour. As will be appreciated by one those of ordinary skill in the art, any deleterious effects of heat accumulate with time. Therefore, when heat is applied, time and temperature will typically be balanced against one another.
There is wide latitude in formulation of all particle-forming compositions of the present invention. Preferably, all non-fused pyrrolocarbazole components in the particle-forming composition are food grade materials or GRAS (Generally Recognized As Safe) materials. Information on GRAS materials can be found in Inactive Ingredient Guide, published by the U.S. Food and Drug Administration (Division of Drug Information Resources, Rockville, Md.), the disclosure of which is hereby incorporated herein by reference in its entirety. Inactive Ingredient Guide provides a listing of all inactive ingredients present in approved or conditionally approved drug products currently marketed for human use.
The compositions of the present invention, preferably contain a surfactant. Although the surfactant may be present in any amount which results in a particle-forming composition, typical compositions contain from about 20% to greater than 99% of a surfactant. Preferably, the amount of surfactant is at least 30%, at least 40%, or at least 50%, depending upon the additional components of the composition.
Surfactants include, but are not limited to, polyoxyethylene stearates, polyoxyethylene castor oil, polyoxyethylene sorbitan fatty acid esters (sorbitans), polyethylene glycol ethers, saturated polyglycolized glycerides, fatty acid esters of polyethylene glycol, hydroxylated lecithins, medium chain monoglycerides, medium chain fatty acid esters, polyethylene/propylene glycol copolymers, polyethylene glycol stearate, d-xe2x88x9d-focopheryl polyethylene glycol succinate, poloxyl stearate (e.g., Myrj(copyright) 52) and poloxyl castor oil.
Polyoxyethylene sorbitan fatty acid esters (polysorbates) are non-ionic surfactants (detergents) that may consist of a mixture of fatty acids. Commercially available examples are Tween(copyright) 20 (polyoxyethylene (20) sorbitan monolaurate), Tween(copyright) 40 (polyoxyethylene (20) sorbitan monopalmitate), and Tween(copyright) 80 (polyoxyethylene (20) sorbitan monooleate).
A preferred polyethylene glycol ether is PEG-4-isooctylphenyl ether, a non-ionic surfactant. Commercially available examples of polyethylene glycol ether surfactants are Triton(copyright) X-100, Triton(copyright) X-114, Triton(copyright) X-405, and Triton(copyright) N-101. Non-ionic surfactants are preferred.
Examples of other useful surfactants are saturated polyglycolized glycerides consisting of mono-, di-, or triglycerides; di-fatty acid esters of polyethylene glycol, e.g., Gelucire(copyright) 44/14; hydroxylated lecithins, e.g., Centrolene(copyright) A; medium chain monoglycerides, e.g., glyceryl monocaprylate (Imwitor(copyright) 308, Capmul(copyright) MCM C-8); medium chain monoglycerides and diglycerides, e.g., glyceryl caprylate/caprate (Capmul(copyright) MCM); polyethylene/propylene glycol copolymers; block copolymers of ethylene oxide and propylene oxide (e.g., Poloxamer 188, Pluronic(copyright) F-68); ethoxylated castor oil (e.g., Cremophor(copyright) EL); and ethoxylated hydroxystearic acid (e.g., Solutol(copyright) HS 15). Some surfactants are solid or semisolid at room temperature, e.g., Poloxamer 188, glyceryl monocaprylate, and Gelucire(copyright) 44/14. Additional surfactants are those found in The Handbook of Pharmaceutical Excipients, 2nd Ed., published by The Pharmaceutical Press, London and American Pharmaceutical Association (1994), a common text in the field, which is hereby incorporated by reference in its entirety.
The particle-forming compositions may also include an organic solvent, a lipid, an antioxidant, or a combination of these components. Such components include those found in The Handbook of Pharmaceutical Excipients, and include any which are known in the art to be acceptable for use in pharmaceutical formulations. The selection of suitable components is within ordinary skill in the art.
In some embodiments of the invention, inclusion of an organic solvent improves solubility of the fused pyrrolocarbazoles in the particle-forming composition. Certain useful organic solvents form a solid (or semi-solid) at room temperature, e.g., polyethylene glycol 1450. The effectiveness of an organic solvent may depend, in part, on the particular fused pyrrolocarbazole included in the particle-forming composition. By way of general guidance, organic solvents include, but are not limited to, propylene carbonate, dimethyl isosorbide, benzyl alcohol, and glycols such as propylene glycol and polyethylene glycol (PEG). As used herein, xe2x80x9cpolyethylene glycolxe2x80x9d or xe2x80x9cPEGxe2x80x9d means a liquid or solid polymer of the general formula H(OCH2CH2)nOH, wherein n is at least 4.
In some embodiments of the invention, a suitable antioxidant is included as a component of the particle-forming composition. As used herein, xe2x80x9cantioxidantxe2x80x9d is intended to indicate any substance useful to retard deterioration by oxidation or to inhibit reactions promoted by oxygen or peroxides. Antioxidants include, but are not limited to, ascorbic acid; fatty acid esters of ascorbic acid, e.g., ascorbyl palmitate; and butylated hydroxyanisole. An antioxidant is particularly useful when the fused pyrrolocarbazole contains a functional group susceptible to oxidation, e.g., a thiol or a thioether. A specific example of such a fused pyrrolocarbazole is the indolocarbazole compound IIa-51, which contains two thioether functionalities. An antioxidant can function either by scavenging oxidative compounds or inhibiting oxidation reactions.
In some embodiments of the invention, a suitable lipid is included as a component of the particle-forming composition. As used herein, xe2x80x9clipidxe2x80x9d is intended to indicate a fat, oil, wax, sterol, glycerol ether, triglyceride, or combination thereof. The inclusion of a lipid can change particle characteristics, including particle size. One way in which a lipid can change particle characteristics is by causing formation of a microemulsion rather than micelles. Lipid-induced changes in particle characteristics can also affect bioavailability.
Although the compositions described herein may conceivably employ any therapeutic substance with poor aqueous solubility characteristics, the particle-forming compositions preferably contain a fused pyrrolocarbazole. Preferably the fused pyrrolocarbazole is present in the particle-forming composition at a concentration of 1 to 300 mg/ml. More preferably, the fused pyrrolocarbazole is present at a concentration of 1 to 100 mg/ml. Even more preferably, the fused pyrrolocarbazole is present at a concentration of about 1 to 50 mg/ml.
As used herein, xe2x80x9cfused pyrrolocarbazolexe2x80x9d is intended to mean a compound having a fused pyrrolocarbazole core structure: 
wherein at least one of G, X, or W is a nitrogen, B is an aryl or heteroaryl group, and * indicates the attachment point of an additional fused ring system.
The core structures provided herein are presented by way of general guidance, and are not to be taken as limiting the scope of the invention. For example, certain cores indicate the presence certain atoms for illustrative purposes. It will be appreciated that such atoms may bonded to additional groups, or may be further substituted without deviating from the spirit of the invention.
Thus, pyrrolocarbazole core structures include, but are not limited to, structures of formula Ia: 
wherein Q may be a moiety containing one or more nitrogens or carbons. Such structures include, but are not limited to, indolocarbazoles, indenocarbazoles, and bridged indenocarbazoles.
As used herein, xe2x80x9cindolocarbazolexe2x80x9d is intended to indicate a compound of formula Ia, wherein Q is nitrogen and Y is a bond: 
These compounds are intended to include, but are not limited to, structures in which the nitrogens of the carbazole and the indole form a cyclic bridged moiety: 
Such bridged structures include, but are not limited to, derivatives of the microbial-derived material referred to as K-252a.
As used herein, xe2x80x9cindenocarbazolexe2x80x9d is intended to indicate a compound of formula Ia in which Q is not nitrogen. These compounds include, but are not limited to, compounds wherein Q is one or more carbons. For example, in certain indenocarbazoles, Q is a single carbon: 
As used herein, xe2x80x9cbridged indenopyrrolocarbazolexe2x80x9d is intended to indicate a compound of formula Ia in which Q is a moiety containing at least one carbon which joins with the nitrogen of the carbazole derivative to form a bridged moeity: 
The fused pyrrolocarbazoles suitable for the particle-forming compositions of the present invention are stable compounds. As used herein xe2x80x9cstable compoundxe2x80x9d or xe2x80x9cstable structurexe2x80x9d is meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.
The fused pyrrolocarbazoles may be further substituted. As used herein, xe2x80x9csubstitutedxe2x80x9d is intended to indicate that one or more hydrogen atoms on the indicated atom is replaced with a selected group referred to herein as a xe2x80x9csubstituentxe2x80x9d, provided that the substituted atom""s valency is not exceeded, and that the substitution results in a stable compound.
As used herein, the term xe2x80x9calkylxe2x80x9d means a straight-chain, cyclic, or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, neopentyl, 1-ethylpropyl, hexyl, octyl, cyclopropyl, and cyclopentyl. The alkyl moiety of alkyl-containing groups, such as alkoxy, alkoxycarbonyl, and alkylaminocarbonyl groups, has the same meaning as alkyl defined above. Lower alkyl groups, which are preferred, are alkyl groups as defined above which contain 1 to 4 carbons.
Alkyl groups and alkyl moieties contained within substituent groups such as aralkyl, alkoxy, arylalkoxy, hydroxyalkoxy, alkoxy-alkoxy, hydroxy-alkylthio, alkoxy-alkylthio, alkylcarbonyloxy, hydroxyalkyl and acyloxy groups may be substituted or unsubstituted. A substituted alkyl group has 1 to 3 independently-selected substituents, preferably hydroxy, lower alkoxy, lower alkoxy-alkoxy, substituted or unsubstituted arylalkoxy-lower alkoxy, substituted or unsubstituted heteroarylalkoxy-lower alkoxy, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heterocycloalkoxy, halogen, carboxyl, lower alkoxycarbonyl, nitro, amino, mono- or di-lower alkylamino, dioxolane, dioxane, dithiolane, dithione, furan, lactone, or lactam.
As used herein, the term xe2x80x9calkenylxe2x80x9d is intended to include straight-chain, cyclic, or branched hydrocarbon chains having at least one carbon-carbon double bond. Examples of alkenyl groups include ethenyl, propenyl, 3-methylbutenyl, and cyclohexenyl groups. As used herein, the term xe2x80x9calkynylxe2x80x9d is intended to include straight-chain, cyclic, or branched hydrocarbon chains having at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl, propynyl, 3-methylbutynyl, and cyclohexynyl groups.
As used herein, the xe2x80x9cacylxe2x80x9d moiety of acyl-containing groups such as acyloxy groups is intended to include a straight-chain, branched, or cyclic alkanoyl group having 1 to 6 carbon atoms, such as formyl, acetyl, propanoyl, butyryl, valeryl, pivaloyl or hexanoyl.
As used herein, the term xe2x80x9ccarbocyclicxe2x80x9d refers to cyclic groups in which the ring portion is composed solely of carbon atoms. These include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexl, cycloheptyl, cyclooctyl. The term xe2x80x9ccarbocyclic aromatic ringxe2x80x9d is intended to include carbocyclic rings which are also aryl rings. The terms xe2x80x9cheterocycloxe2x80x9d and xe2x80x9cheterocyclicxe2x80x9d refer to cyclic groups in which the ring portion includes at least one heteroatom such as O, N, or S. Heterocyclyl groups include heteroaryl and heteroalkyl groups.
As used herein the term xe2x80x9carylxe2x80x9d means an aromatic ring having 6 to 12 carbon atoms such as phenyl, biphenyl and naphthyl. Preferred aryl groups include unsubstituted or substituted phenyl and naphthyl groups. The term xe2x80x9cheteroarylxe2x80x9d as used herein denotes an aryl group in which one or more ring carbon atoms is replaced by a hetero (i.e., non-carbon) atom such as O, N or S. Preferred heteroaryl groups include pyridyl, pyrimidyl, pyrrolyl, furyl, thienyl, imidazolyl, triazolyl, tetrazolyl, quinolyl, isoquinolyl, benzoimidazolyl, thiazolyl, pyrazolyl, and benzothiazolyl groups. The term xe2x80x9cheteroalkylxe2x80x9d denotes a cycloalkyl group in which one or more ring carbon atoms is replaced by hetero atoms such as O, N, or S.
As used herein, the term xe2x80x9caralkylxe2x80x9d (or xe2x80x9carylalkylxe2x80x9d) is intended to denote a group having from 7 to 15 carbons, consisting of an alkyl group that bears an aryl group. Examples of aralkyl groups include, but are not limited to, benzyl, phenethyl, benzhydryl and naphthylmethyl groups. Substituted aryl, substituted heterocyclic and substituted aralkyl groups each have 1 to 3 independently selected substituents that are preferably lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, nitro, amino, mono- or di-lower alkylamino, and halogen.
Preferred heterocyclic groups formed with a nitrogen atom include pyrrolidinyl, piperidinyl, piperidino, morpholinyl, morpholino, thiomorpholino, N-methylpiperazinyl, indolyl, isoindolyl, imidazole, imidazoline, oxazoline, oxazole, triazole, thiazoline, thiazole, isothiazole, thiadiazoles, triazines, isoxazole, oxindole, indoxyl, pyrazole, pyrazolone, pyrimidine, pyrazine, quinoline, iosquinoline, and tetrazole groups. Preferred heterocyclic groups formed with an oxygen atom include furan, tetrahydrofuran, pyran, benzofurans, isobenzofurans, and tetrahydropyran groups. Preferred heterocyclic groups formed with a sulfur atom include thiophene, thianaphthene, tetrahydrothiophene, tetrahydrothiapyran, and benzothiophenes.
As used herein, xe2x80x9chydroxyalkylxe2x80x9d groups are alkyl groups that have a hydroxyl group appended thereto. As used herein, xe2x80x9chydroxyalkoxyxe2x80x9d groups are alkoxy groups that have a hydroxyl group appended thereto. As used herein, xe2x80x9chalogenxe2x80x9d refers to fluorine, chlorine, bromine and iodine.
As used herein, the term xe2x80x9cheteroarylalkylxe2x80x9d means an arylalkyl group that contains a heteroatom in the aryl moiety. The term xe2x80x9coxylxe2x80x9d denotes the presence of an oxygen atom. Thus, xe2x80x9calkoxyxe2x80x9d groups are alkyl groups that are attached through an oxygen atom, and xe2x80x9ccarbonyloxyxe2x80x9d groups are carbonyl groups that are attached through an oxygen atom.
As used herein, the terms xe2x80x9cheterocycloalkylxe2x80x9d and xe2x80x9cheterocycloalkoxyxe2x80x9d mean an alkyl or an alkoxy group that has a heterocyclo group attached to the alkyl moiety thereof, and the term xe2x80x9carylalkoxyxe2x80x9d means an alkoxy group that has an aryl group attached to the alkyl moiety thereof. As used herein, the term xe2x80x9calkylcarbonyloxyxe2x80x9d means a group of formula xe2x80x94Oxe2x80x94C(xe2x95x90O)-alkyl.
As used herein, the term xe2x80x9calkyloxy-alkoxyxe2x80x9d denotes an alkoxy group that contains an alkyloxy substituent attached to its alkyl moiety. The term xe2x80x9calkoxy-alkylthioxe2x80x9d means an alkylthio group (i.e., a group of formula xe2x80x94S-alkyl) that contains an alkoxy substituent attached to its alkyl moiety. The term xe2x80x9chydroxy-alkylthioxe2x80x9d means an alkylthio group (i.e., a group of formula xe2x80x94S-alkyl) that contains a hydroxy substituent attached to its alkyl moiety.
As used herein, the term xe2x80x9cmonosaccharidexe2x80x9d has its accustomed meaning as a simple sugar. As used herein, the term xe2x80x9camino acidxe2x80x9d denotes a molecule containing both an amino group and a carboxyl group. Embodiments of amino acids include a-amino acids; i.e., carboxylic acids of general formula HOOCxe2x80x94CH(NH2)-(side chain). Side chains of amino acids include naturally occurring and non-naturally occurring moieties. Non-naturally occurring (i.e., unnatural) amino acid side chains are moieties that are used in place of naturally occurring amino acid side chains in, for example, amino acid analogs. See, for example, Lehninger, Biochemistry, Second Edition, Worth Publishers, Inc, 1975, pages 73-75, incorporated by reference herein. In certain embodiments, substituent groups for the compounds described herein include the residue of an amino acid after removal of the hydroxyl moiety of the carboxyl group thereof; i.e., groups of Formula xe2x80x94C(xe2x95x90O)CH(NH2)-(side chain).
The fused pyrrolocarbazoles are preferably present in the compositions described herein in a therapeutically effective amount. As used herein, a xe2x80x9ctherapeutically effective amountxe2x80x9d refers to an amount of compound effective to prevent or treat the symptoms of particular disorder. Such disorders include, but are not limited to, those pathological and neurological disorders associated with the aberrant activity of target receptors, wherein the treatment or prevention comprises inhibiting, inducing, or enhancing the activity thereof by contacting the receptor with an active drug substance. As will be readily understood, the concentration and dosages of the fused pyrrolocarbazoles will depend upon factors such as the total dosage of the drug to be administered, the chemical characteristics of the compounds employed, the route of administration, the age, body weight and symptoms of the patient, etc. By way of general guidance, human doses may range from about 0.1 mg to about 1000 mg administered per day. Preferably, the dosage is about 1 to about 500 mg administered two times a day. Even more preferably, the dosage is about 10 mg to about 300 mg, two times per day.
The fused pyrrolocarbazole may be present in various forms as will be appreciated by the skilled artisan. Such forms include, but are not limited to, pharmaceutically acceptable salts, prodrugs, polymorphs, stereoisomers, and the like. As used herein, the term xe2x80x9cpharmaceutically acceptablexe2x80x9d refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ration.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
The fused pyrrolocarbazoles of the present invention may exist in prodrug form. As used herein, xe2x80x9cprodrugxe2x80x9d is intended to include any covalently bonded carriers which release the active parent drug according to Formula (I) or other formulas or compounds of the present invention in vivo when such prodrug is administered to a mammalian subject. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention contemplates prodrugs of the claimed compounds, compositions containing the same, and methods of delivering the same. Prodrugs of a compound of the present invention; for example Formula I, may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
Accordingly, prodrugs include, for example, compounds of the present invention wherein a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or carboxylic acid, respectively. Examples include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups; and alkyl, carbocyclic, aryl, and alkylaryl esters such as methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl, benzyl, and phenethyl esters, and the like.
The compounds of the present invention may be prepared in a number of ways well known to those skilled in the art. The compounds can be synthesized, for example, by the methods described below, or variations thereon as appreciated by the skilled artisan. All processes disclosed in association with the present invention are contemplated to be practiced on any scale, including milligram, gram, multigram, kilogram, multikilogram or commercial industrial scale.
It will be appreciated that the compounds of the present invention may contain one or more asymmetrically substituted carbon atoms, and may be isolated in optically active or racemic forms. Thus, all chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. It is well known in the art how to prepare and isolate such optically active forms. For example, mixtures of stereoisomers may be separated by standard techniques including, but not limited to, resolution of racemic forms, normal, reverse-phase, and chiral chromatography, preferential salt formation, recrystallization, and the like, or by chiral synthesis either from chiral starting materials or by deliberate synthesis of target chiral centers.
As will be readily understood, functional groups present may contain protecting groups during the course of synthesis. For example, the amino acid side chain substituents of the compounds of Formula Ia can be substituted with protecting groups such as benzyloxycarbonyl or t-butoxycarbonyl groups. Protecting groups are known per se as chemical functional groups that can be selectively appended to and removed from functionalities, such as hydroxyl groups and carboxyl groups. These groups are present in a chemical compound to render such functionality inert to chemical reaction conditions to which the compound is exposed. Any of a variety of protecting groups may be employed with the present invention. Preferred protecting groups include the benzyloxycarbonyl (Cbz; Z) group and the tert-butyloxycarbonyl (Boc) group. Other preferred protecting groups according to the invention may be found in Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis 2d. Ed., Wiley and Sons, 1991.
Fused pyrrolocarbazoles, such as indolocarbazoles may be synthesized by methods taught, for example, in U.S. Pat. Nos. 4,923,986; 4,877,776; 5,093,330; 5,461,146; 5,468,872; 5,621,100; 5,621,101; 5,516,771; and 5,599,808; and PCT publication Nos. WO 93/08809 and WO 97/46565, the discloses of which are hereby incorporated herein by reference in their entirety. Additional methods of preparation are set forth in Moody et al., J. Org. Chem. 57:2105-2114 (1992), also incorporated herein by reference.
Fused pyrrolocarbazoles, such as indenocarbazoles, as well as additional compounds wherein Q is not a single nitrogen, may be synthesized by methods taught, for example, in U.S. Pat. Nos. 5,475110; 5,591,855; 5,594,009; 5,705,511; 5,616,724; and 5,801,190; the disclosures of which are hereby incorporated herein by reference in their entirety.
Fused pyrrolocarbazoles, such as bridged indenocarbazoles, may be prepared by methods taught, for example, in U.S. patent application Ser. No. 09/325,140, the disclosure of which is hereby incorporated herein by reference in its entirety.
The fused pyrrolocarbazoles disclosed in all foregoing references are contemplated for use in the particle-forming compositions of the present invention. Other exemplary fused pyrrolocarbazoles are the indolocarbazoles set forth in Tables I-A and I-B, wherein each entry corresponds to the accompanying structure.
Certain preferred indolocarbazoles are compounds designated by formula IIa-4, IIa-12, and IIa-51 having the following structures. 
The non-aqueous particle-forming compositions of the invention provide greatly improved bioavailability of fused pyrrolocarbazoles. For example, in water Compound IIa-12 has essentially no solubility. In pure Tween 80, it has a solubility of 28.43 mg/ml. When placed directly in an aqueous solution of 2% Tween 80, Compound IIa-12 has a solubility of 0.18 mg/ml. When initially dissolved in Tween 80 (a particle-forming composition) and subsequently diluted 50-fold with water (to produce an aqueous solution of 2% Tween 80), the final solubility is 0.57 mg/ml.
Thus, dissolving the fused pyrrolocarbazole initially in this particular particle-forming composition achieves a better than 3.2-fold increase in fused pyrrolocarbazole concentration in the final solution. Because initial contact with an aqueous medium occurs in vitro or in vivo, the non-aqueous particle-forming compositions are useful for therapeutic administration of a fused pyrrolocarbazole to a mammal.
The present invention also features a method of forming a stable suspension of fused pyrrolocarbazole-containing particles. The method typically includes: (a) dissolving an fused pyrrolocarbazole in a non-aqueous liquid containing a surfactant in an amount from about 20% to greater than 99%, thereby forming an fused pyrrolocarbazole-containing, particle-forming composition, and (b) contacting the particle-forming composition with an aqueous medium. The particle-forming composition can be contacted with the aqueous medium in vitro or in vivo. Preferably, the amount of surfactant is at least 30%, and more preferably, it is at least 40%, with 50% being particularly preferred. The particle-forming composition optionally includes an organic solvent, a lipid, an antioxidant, or a combination of those components.
The invention also features a method of treating a neurological disease or disorder in a mammal, e.g., a human. The method includes formulating a fused pyrrolocarbazole in a non-aqueous, fused pyrrolocarbazole-containing, particle-forming composition containing a surfactant in an amount of at least 20% (w/w), and administering a therapeutically effective amount of the particle-forming composition to the mammal. In one embodiment of the method, the particle-forming composition is contacted with an aqueous medium in vitro, to form a stable suspension. A therapeutically effective amount of the stable suspension is then administered to the mammal. In an alternative embodiment, a therapeutically effective amount of the particle-forming composition is administered directly to the mammal, where it contacts an aqueous medium in vivo.
The invention also features a method of treating cancer, including prostate cancer, in a mammal, e.g., a human. The method includes formulating a fused pyrrolocarbazole in a non-aqueous, fused pyrrolocarbazole-containing, particle-forming composition containing a surfactant in an amount of at least 20% (w/w), and administering a therapeutically effective amount of the particle-forming composition to the mammal. In one embodiment of the method, the particle-forming composition is contacted with an aqueous medium in vitro, to form a stable suspension. A therapeutically effective amount of the stable suspension is then administered to the mammal. In an alternative embodiment, a therapeutically effective amount of the particle-forming composition is administered directly to the mammal, where it contacts an aqueous medium in vivo.